TY - JOUR
T1 - ALDH2 contributes to melatonin-induced protection against APP/PS1 mutation-prompted cardiac anomalies through cGAS-STING-TBK1-mediated regulation of mitophagy
AU - Wang, Shuyi
AU - Wang, Lin
AU - Qin, Xing
AU - Turdi, Subat
AU - Sun, Dongdong
AU - Culver, Bruce
AU - Reiter, Russel J.
AU - Wang, Xiaoming
AU - Zhou, Hao
AU - Ren, Jun
N1 - Funding Information:
Effect of melatonin on mitochondrial integrity, cardiomyocyte function, and intracellular Ca2+handling To assess the potential mechanisms involved in melatonin-induced benefits, myocardial ultrastructure, mitochondrial integrity and function, and cardiomyocyte mechanical properties were evaluated. The data shown in Fig. 3a–c revealed that the APP/PS1 mutation overtly interrupted myofilament alignment and mitochondrial ultrastructure, as evidenced by the increased numbers and sizes of mitochondria. Although melatonin did not affect myocardial ultrastructure in the controls, it ablated APP/PS1-induced myocardial ultrastructural anomalies. This was supported by mitochondrial assessments. APP/PS1 reduced aconitase activity, the JC-1 ratio, and levels of mitochondrial uncoupling protein 2 (UCP2) and peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α), the effects of which were reversed by melatonin, with little effect of melatonin in the controls (Fig. 3d–h). Assessment of cardiomyocyte mechanics revealed that APP/PS1 mutation overtly impaired cardiomyocyte contractility and intracellular Ca2+, as evidenced by decreases in peak shortening (PS), maximal velocity of shortening and relengthening (±dL/dt), and the electrically stimulated rise in intracellular Ca2+ (ΔFFI) without affecting time-to-PS (TPS), time-to-90% relengthening (TR90), resting intracellular Ca2+ level, or the intracellular Ca2+ decay rate. Consistent with its effect on myocardial contractility, melatonin abrogated APP/PS1-induced defects in cardiomyocyte contractility and intracellular Ca2+ without eliciting any effect in the controls (Fig. 3i–p).
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - Ample clinical evidence suggests a high incidence of cardiovascular events in Alzheimer’s disease (AD), although neither precise etiology nor effective treatment is available. This study was designed to evaluate cardiac function in AD patients and APP/PS1 mutant mice, along with circulating levels of melatonin, mitochondrial aldehyde dehydrogenase (ALDH2) and autophagy. AD patients and APP/PS1 mice displayed cognitive and myocardial deficits, low levels of circulating melatonin, ALDH2 activity, and autophagy, ultrastructural, geometric (cardiac atrophy and interstitial fibrosis) and functional (reduced fractional shortening and cardiomyocyte contraction) anomalies, mitochondrial injury, cytosolic mtDNA buildup, apoptosis, and suppressed autophagy and mitophagy. APP/PS1 mutation downregulated cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) levels and TBK1 phosphorylation, while promoting Aβ accumulation. Treatment with melatonin overtly ameliorated unfavorable APP/PS1-induced changes in cardiac geometry and function, apoptosis, mitochondrial integrity, cytosolic mtDNA accumulation (using both immunocytochemistry and qPCR), mitophagy, and cGAS-STING-TBK1 signaling, although these benefits were absent in APP/PS1/ALDH2−/− mice. In vitro evidence indicated that melatonin attenuated APP/PS1-induced suppression of mitophagy and cardiomyocyte function, and the effect was negated by the nonselective melatonin receptor blocker luzindole, inhibitors or RNA interference of cGAS, STING, TBK1, and autophagy. Our data collectively established a correlation among cardiac dysfunction, low levels of melatonin, ALDH2 activity, and autophagy in AD patients, with compelling support in APP/PS1 mice, in which melatonin rescued myopathic changes by promoting cGAS-STING-TBK1 signaling and mitophagy via an ALDH2-dependent mechanism.
AB - Ample clinical evidence suggests a high incidence of cardiovascular events in Alzheimer’s disease (AD), although neither precise etiology nor effective treatment is available. This study was designed to evaluate cardiac function in AD patients and APP/PS1 mutant mice, along with circulating levels of melatonin, mitochondrial aldehyde dehydrogenase (ALDH2) and autophagy. AD patients and APP/PS1 mice displayed cognitive and myocardial deficits, low levels of circulating melatonin, ALDH2 activity, and autophagy, ultrastructural, geometric (cardiac atrophy and interstitial fibrosis) and functional (reduced fractional shortening and cardiomyocyte contraction) anomalies, mitochondrial injury, cytosolic mtDNA buildup, apoptosis, and suppressed autophagy and mitophagy. APP/PS1 mutation downregulated cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) levels and TBK1 phosphorylation, while promoting Aβ accumulation. Treatment with melatonin overtly ameliorated unfavorable APP/PS1-induced changes in cardiac geometry and function, apoptosis, mitochondrial integrity, cytosolic mtDNA accumulation (using both immunocytochemistry and qPCR), mitophagy, and cGAS-STING-TBK1 signaling, although these benefits were absent in APP/PS1/ALDH2−/− mice. In vitro evidence indicated that melatonin attenuated APP/PS1-induced suppression of mitophagy and cardiomyocyte function, and the effect was negated by the nonselective melatonin receptor blocker luzindole, inhibitors or RNA interference of cGAS, STING, TBK1, and autophagy. Our data collectively established a correlation among cardiac dysfunction, low levels of melatonin, ALDH2 activity, and autophagy in AD patients, with compelling support in APP/PS1 mice, in which melatonin rescued myopathic changes by promoting cGAS-STING-TBK1 signaling and mitophagy via an ALDH2-dependent mechanism.
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U2 - 10.1038/s41392-020-0171-5
DO - 10.1038/s41392-020-0171-5
M3 - Article
C2 - 32703954
AN - SCOPUS:85086606991
VL - 5
JO - Signal Transduction and Targeted Therapy
JF - Signal Transduction and Targeted Therapy
SN - 2095-9907
IS - 1
M1 - 119
ER -